Bone fractures are common traumatic injuries that often cause temporary disability. In healthy children and adults, fractures normally heal without sequelae, though the temporary disability can lead to muscle atrophy, rehabilitation, and lost time from the work place. Advancing age and other co-morbid conditions, such as diabetes, can greatly increase fracture healing times and reduce overall rates for successful healing. In addition, severe muscle atrophy and prolonged stays at hospitals and rehabilitation or nursing homes are especially common in elderly and diabetic patients. A 25% reduction in healing time would reduce complications and enable people to return to their normal routines much sooner, while dramatically reducing costs associated with healing. Thus a therapy that would accelerate the normal healing process would be of significant benefit to many of the 10 million Americans who suffer a fracture each year. Presently, no such therapy exists. We previously demonstrated that loss or inhibition of COX-2 severely impairs fracture healing. Our tests to understand the mechanism of this impairment led us to test the effects of 5-lipoxygenase (5-LO) inhibitors on the rate of fracture healing. This was based on the idea that when COX-2 is inhibited, arachidonic acid is shunted into the 5-LO pathway and the resulting metabolites slow fracture healing, as detailed in the Background section of this proposal. Following this idea, we have identified a 5-LO inhibitor (A-79175) that reduces the time for fracture healing in rats by 25%, reduced non-unions to 0% from 33% at the experimental endpoint, and increased measures of healed bone strength by 50-90% compared to untreated controls. We have developed a use patent estate for this compound and 5-LO inhibitors in general for bone healing. The composition of matter patent on this compound has lapsed so we can use this compound without having to obtain a license. This compound is a small molecule and is orally available. A-79175 has already successfully passed Phase I human clinical trials for asthma. The half life and other drug-like properties of this molecule, including potency, are well suited for the indication of treating fractures. The aim of this proposal is to demonstrate that A-79175 will accelerate and enhance fracture healing in a higher animal model. A positive finding in this animal model will support the use of 5-LO inhibitors as a therapeutic strategy for fracture care, position A-79175 for an IND application for proof of concept testing in humans, and move our company toward further successful development of the first drug to enhance the rate of bone healing. Increasing the rate of healing could have a large impact on those with factures by improving patient quality of life, reducing recuperation time, muscle wasting, rehabilitation time, incidence of complications, overall health care costs, and more. PUBLIC HEALTH RELEVANCE: Project Narrative We have identified an orally delivered drug that accelerates and enhances fracture healing in small animal models. Bone fractures are common traumatic injuries. Complications associated with fractures include delayed healing or failed healing (non-unions) and attending disability and muscle atrophy. Common pathological conditions such as osteoporosis and diabetes increase the incidence of fractures or significantly impair healing. Presently, there is no cost-effective therapy to prospectively treat fractures to reduce time to healing or reduce the incidence of delayed healing or non-union. This project will test our newly identified therapy in a clinically relevant animal model to confirm our previous findings and justify testing in humans.